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An erythroid chaperone that facilitates folding of alpha-globin subunits for hemoglobin synthesis

Citation

Yu, X and Kong, Y and Dore, LC and Abdulmalik, O and Katein, AM and Zhou, S and Choi, JK and Gell, DA and Mackay, JP and Gow, AJ and Weiss, MJ, An erythroid chaperone that facilitates folding of alpha-globin subunits for hemoglobin synthesis, Journal of Clinical Investigation, 117, (7) pp. 1856-1865. ISSN 0021-9738 (2007) [Refereed Article]

DOI: doi:10.1172/JCI31664

Abstract

Erythrocyte precursors produce abundant α- and β-globin proteins, which assemble with each other to form hemoglobin A (HbA), the major blood oxygen carrier. αHb-stabilizing protein (AHSP) binds free α subunits reversibly to maintain their structure and limit their ability to generate reactive oxygen species. Accordingly, loss of AHSP aggravates the toxicity of excessive free α-globin caused by β-globin gene disruption in mice. Surprisingly, we found that AHSP also has important functions when free α-globin is limited. Thus, compound mutants lacking both Ahsp and 1 of 4 α-globin genes (genotype Ahsp-/-α-globin -/-α/αα) exhibited more severe anemia and Hb instability than mice with either mutation alone. In vitro, recombinant AHSP promoted folding of newly translated α-globin, enhanced its refolding after denaturation, and facilitated its incorporation into HbA. Moreover, in erythroid precursors, newly formed free α-globin was destabilized by loss of AHSP. Therefore, in addition to its previously defined role in detoxification of excess α-globin, AHSP also acts as a molecular chaperone to stabilize nascent α-globin for HbA assembly. Our findings illustrate what we believe to be a novel adaptive mechanism by which a specialized cell coordinates high-level production of a multisubunit protein and protects against various synthetic imbalances.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Structural Biology (incl. Macromolecular Modelling)
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Biological Sciences
Author:Gell, DA (Dr David Gell)
ID Code:64531
Year Published:2007
Web of Science® Times Cited:72
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-08-12
Last Modified:2011-07-29
Downloads:0

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